Pyrazine sulfoxides,

By aminolysis of pyrazine sulfoxides or sulfones (nuclear primary, secondary, tertiary) Section 6.4. 

In pyridine- X-C interactions, the C - X moiety is roughly coplanar with the pyridine and the two C-N- X angles are approximately 120° [129,143, 144]. The same holds for other nitrogen heteroaromatics (e.g. pyrazine, quinoline, etc.) [145-147]. A carbonyl group pins the donors after a trigonal planar geometry and works either as a mono- [148,149] or bidentate XB acceptor [150]. Sulfoxides behave similarly [151,152] and imines form XB along the expected axis of the lone pair [153]. 

The remaining minor routes appear to be represented in recent literature only by the reaction of ethyl 2-pyrazinecarboxylate (67) with prelithiated dimethyl sulfoxide (DMSO) in THF at 20°C during 3 h to afford 2-(methylsulfinylacetyl)pyrazine (68) (30%) 896 and by the reaction of chloropyrazines (69) with sodium p-acetamidoben-zenesulfinate to give the corresponding p-acetamidophenylsulfonylpyrazines (70).882... 

Since the excellent 1973 summary of azido—tetrazolo valence-tautomerism in nitrogenous heterocycles,1713 little has been added to our knowledge of factors governing such tautomerism (227 228) in the pyrazine series. However, it has been shown by NMR studies that 2-azidopyrazine 4-oxide (229) exists as such in chloroform, as tetrazolo[l,5-a]pyrazine 7-oxide (230) in dimethyl sulfoxide, and as a mixture in acetone.272 For obvious pragmatic reasons, all such compounds are named as azidopyrazines in this book, irrespective of their predominant structures. 

Radical nucleophile oxidation based on one-electron oxidation, known as the Minisci reaction, is employed for the functionalization of /V-heterocycles with acidic hydrogen peroxide in the presence of iron(II) salts (Figure 3.112).472 A range of A-heterocycles (pyridines, pyrazines, quinolines, etc.) which are activated towards attack by nucleophilic radicals when protonated are suited to this chemistry. The Minisci reaction is suitable for the preparation of carboxylic amides (from formamide), carboxylic esters (from pyruvic esters via a hydroxyhydroperoxide), aldehydes (from 1,3,5-trioxane) and alkylated pyridines (either from carboxylic acids or from alkyl iodides in dimethyl sulfoxide).473 The latter reaction uses dimethyl sulfoxide as the source of methyl radical (Figure 3.112). 

An large number of pyrazines were subjected to X-ray crystallographic analysis. Those in the realm of metal complexes included [/i-2,3,5,6-tetrakis(2-pyridyl)pyrazine]bis[chloroplatinum(II)] bis[trichloro(dimethyl sulfoxide-ir5)platinate(II)] 152 <03AX(E)411>, tetraaqua-1,2,4,5-benzenetetracarboxylato(pyrazine)dicobalt(II) dihydrate <03AX(E)841>, polymeric... 

Methylpyrazine is methylated with methyl iodide in dimethyl sulfoxide at room temperature to give l-methyl-3-methylpyrazinium iodide and i-methyl-2-methyl-pyrazinium iodide, in a ratio of 3.9 I. The rate of methylation relative to pyrazine was 2.06 (666). The reaction of 2,5-dimethylpyrazine with iodo- or bromoacetic acid to give the 1,2,5-trimethylpyrazinium salt has been investigated (3). A kinetic study of the reaction of sodium hydroxide on quaternary pyrazinium salts (667, 668) has been made using a conductivity method to follow the progress of the reaction (11=5 12). In the case of 1,2,5-trimethylpyrazinium hydroxide, equilibrium lies toward (11), which slowly disappears, presumably forming the ether (13) (668). When 1,2,5-trimethylpyrazinium bromide was heated in a sealed tube trimethyl- and tetramethylpyrazine were produced (660). 

Monomethiodides of pyrazine and methylpyrazines have been readily prepared (3, 32, 272, 565, 660). Rates and position of quatemization of 2-substituted pyrazines with methyl iodide in dimethyl sulfoxide at room temperature have been determined by a kinetic competition method (666) 2Hnethylpyrazine gave 13-dimethylpyrazinium iodide as the major product (704), with some 1,2-dimethylpyrazinium iodide (666). 

Rates of methylation (from n.m.r. studies) of 2-fluoro- and 2-chloropyrazines with methyl iodide in dimethyl sulfoxide at room temperature relative to pyrazine have been determined as 0.16 and 0.15, respectively (666). Methylation of 2-chloropyrazine with methyl iodide in benzene at reflux gave one methiodide (912). 2-Chloropyrazine also formed a p-fluorophenacyl bromide salt (913). 

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Methylation (666, 912) of 2-methoxypyrazine with methyl iodide in dimethyl sulfoxide at room temperature gave 3-methoxy-l-methylpyrazinium iodide with a rate of methylation relative to pyrazine of 1.05 (666). 2-Methoxypyrazine with tetracyanoethylene oxide gave a small yield of 3 ethoxypyrazinium dicyano-methylide (53) (1094). Alkylation of 2-methoxypyrazine with ethyl methyl ketone in the presence of sodium in liquid ammonia to give 2-s-butyl-6-methoxypyrazine (17%) has been described (614). The reactions of 3-hydroxy-2,5-dimethylpyrazine and alkylhalides have been examined (1095). 

Proton magnetic resonance measurements in dimethyl sulfoxide indicate that 2-aminopyrazine and its 3-methyl derivative exist predominantly in the amino form (979, 1086), in agreement with theoretical and experimental electronic spectra (1083). Proton magnetic resonance analysis of the methylation of 2-aminopyrazine with methyl iodide in dimethyl sulfoxide at room temperature showed it to be methylated 8.8 times as fast as pyrazine to give both 3-amino-l-methyl- and 2-amino-l -methylpyrazinium iodides in the ratio 2.9 I (666). Proton magnetic resonance spectra of ionized 2-aminopyrazine in liquid ammonia have also been reported (665). 

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